A DLBCL Prognostic model superior to the IPI score: Mechanistic study and clinical validation based on RFC2- and RFC4-mediated DNA damage repair.

​Approximately 30% to 40% of patients with Diffuse Large B-cell Lymphoma (DLBCL) experience treatment failure, whereas the current International Prognostic Index (IPI) fails to adequately reflect the intrinsic biological features. This study aimed to investigate the prognostic value of Replication Factor C genes (RFCs) in DLBCL and construct a prognostic risk model. Three DLBCL datasets were downloaded from the Gene Expression Omnibus (GEO) database (GSE181063, GSE10846, GSE31312). Multivariate Cox proportional hazards regression analysis identified high expression of RFC2 and RFC4 as independent adverse prognostic factors (RFC2: HR = 1.46, P = 0.037; RFC4: HR = 1.36, P = 0.034), which were significantly associated with age ≥ 60 years, elevated lactate dehydrogenase (LDH) levels, and poor Eastern Cooperative Oncology Group (ECOG) performance status. Mechanistically, the RFC2 high-expression group exhibited a significant increase in tumor mutational burden (TMB). Protein-protein interaction (PPI) analysis revealed that RFC2 and RFC4 interact with CHTF18, PCNA, and other proteins to maintain genomic stability. Gene set enrichment analysis (GSEA) indicated that RFC2 and RFC4 high-expression groups were enriched in the DNA replication and DNA damage repair (DDR) pathways. Competing endogenous RNA (ceRNA) network analysis predicted miR-34a-5p as an upstream regulator; PARD6G-AS1, TERC, and LINC00662 upregulating RFC2 and RFC4 by sponging miR-34a-5p. The RFC-based prognostic model significantly stratified high- and low-risk patients, with superior predictive performance compared to the IPI score. Validation in our clinical cohort confirmed that the high-risk group had significantly shorter overall survival (OS) (P = 0.003). This study provides a novel tool for individualized prognostic assessment in DLBCL and suggests RFC2 and RFC4 as potential therapeutic targets.